Omidenepag Isopropyl in Latanoprost Low/Nonresponders With Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 3, Nonrandomized, Two-Phase, Open-Label Study.

PRCIS: This study demonstrates the efficacy and safety of once-daily 0.002% omidenepag isopropyl (OMDI) in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) who do not respond or respond poorly to latanoprost. PURPOSE: The purpose of this study was to evaluate the intraocular pressure (IOP)-lowering efficacy and safety of OMDI in latanoprost low/nonresponders with POAG or OHT. MATERIALS AND METHODS: Phase 3, nonrandomized, 2-phase, open-label, multicenter study (NCT03697811) in the United States. Key inclusion criteria included individuals aged 18 years or above, POAG or OHT diagnosis in both eyes, IOP ≥22 mm Hg in ≥1 eye, and ≤34 mm Hg in both eyes at all time points. Overall, 107 patients were enrolled; 104 completed treatment. Included a screening period (≤35-day washout period and 8-week latanoprost run-in period) and a 3-month treatment period comprising one drop of OMDI 0.002% once daily in both eyes. The primary study endpoint was changed from baseline in the mean diurnal (MD) IOP at month 3. Safety endpoints included incidence of adverse events, serious adverse events, and adverse drug reactions. RESULTS: At baseline (visit 4), 75 (70.1%) patients had POAG, 32 (29.9%) had OHT, and 68 (63.6%) had prior use of prostaglandin/prostaglandin analogs (37.4% of whom used latanoprost). The mean (SD) baseline MD IOP was 23.34 mm Hg (2.12). The mean (SD) 3-month (visit 7) MD IOP change from baseline (following latanoprost run-in period and OMDI treatment period) was an additional decrease of 2.96 mm Hg (2.83) ( P <0.0001). No significant safety issues were reported during OMDI treatment. CONCLUSIONS: These data demonstrate OMDI efficacy and safety in latanoprost low/nonresponders with POAG or OHT, suggesting OMDI is a treatment option in the patient population in this study.

Intraocular pressure-lowering effect of omidenepag isopropyl in latanoprost non-/low-responder patients with primary open-angle glaucoma or ocular hypertension: the FUJI study.

PURPOSE: Omidenepag isopropyl (OMDI) is the prodrug of omidenepag, a selective, non-prostaglandin, prostanoid EP2 receptor agonist, which has been shown to lower intraocular pressure (IOP) in patients with glaucoma and ocular hypertension (OHT). This study evaluated the efficacy and safety of OMDI ophthalmic solution 0.002% in patients with primary open-angle glaucoma or OHT who were non-/low responders to latanoprost. STUDY DESIGN: Open-label, multicenter, Phase 3 study (NCT02822742). METHODS: Following 1-4-week washout, patients were treated with latanoprost ophthalmic solution 0.005% during an 8-week run-in period. Patients with ≤15% IOP reduction at the end of the run-in (indicating non-/low response) received OMDI 0.002% (one drop once daily for 4 weeks). The primary endpoint was the change from baseline in mean diurnal IOP at Week 4. RESULTS: In total, 26 patients were treated with OMDI; two withdrew owing to lack of efficacy. The mean diurnal IOP at baseline (end of latanoprost run-in) was 23.1 mmHg (7.6% IOP reduction from end of washout) indicating non-/low response to latanoprost. After 4 weeks of OMDI treatment, mean diurnal IOP was significantly reduced from baseline (-2.99 mmHg; P < 0.0001). No serious adverse events were reported. Adverse events occurred in five patients (19.2%); adverse drug reactions (anterior chamber cell, conjunctival hyperemia, and erythema of eyelid) occurred in two patients (7.7%) and were mild in severity. CONCLUSIONS: In this study, OMDI 0.002% demonstrated a clinically significant reduction in IOP and was well tolerated in patients with primary open-angle glaucoma and OHT who were non-/low responders to latanoprost.

Changes in ocular signs and symptoms in patients switching from bimatoprost-timolol to tafluprost-timolol eye drops: an open-label phase IV study.

OBJECTIVES: Bimatoprost-timolol (bimatoprost 0.03%-timolol 0.5% fixed-dose combination [FDC]) and tafluprost-timolol (tafluprost 0.0015%-timolol 0.5% FDC) eye drops are currently the only topical intraocular pressure (IOP)-reducing therapies available as preservative-free (PF) prostaglandin and timolol FDC. The aim of this study was to investigate changes to ocular signs and symptoms when patients with ocular hypertension (OH) or open-angle glaucoma (OAG) switched from PF or benzalkonium chloride (BAK)-preserved bimatoprost-timolol to PF tafluprost-timolol eye drops. DESIGN: This was a 12-week, open-label, phase IV study. SETTING: Sixteen centres in Finland, Germany, Italy and the UK. PARTICIPANTS: Patients with OH or OAG (IOP on medication ≤21 mm Hg), treated with PF or BAK-preserved bimatoprost-timolol for ≥4 weeks before screening, and presenting with conjunctival hyperaemia and ≥1 ocular symptom. INTERVENTIONS: Patients were switched to PF tafluprost-timolol once daily in the treated eye(s). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoints were change from screening to week 12 in conjunctival hyperaemia and worst ocular symptom. The secondary outcome measures were changes from screening in ocular signs (other than conjunctival hyperaemia) and symptoms at week 12. RESULTS: Of 123 enrolled patients, 121 were included in the intention-to-treat dataset, of which all were Caucasian and 54.5% were female; 76 patients used BAK-preserved bimatoprost-timolol and 45 used PF drops. Conjunctival hyperaemia and severity of worst ocular symptom following switch to PF tafluprost-timolol significantly reduced from screening to week 12 in all patients (p<0.001). The percentage of patients with ocular signs and symptoms was significantly reduced at week 12 compared with screening (p<0.001). IOP was not affected by the change of treatment. CONCLUSIONS: Switching from BAK-preserved or PF bimatoprost-timolol to tafluprost-timolol reduced both signs and symptoms of ocular surface disease with no clinically relevant effect on IOP. TRIAL REGISTRATION NUMBER: EudraCT2014-005273-37; Results.

Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: results of an open-label observational study.

BACKGROUND: Efficacy, tolerability and safety of the novel preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% (Taptiqom®) were investigated in an observational study in Germany. OBJECTIVE: To assess efficacy, tolerability and safety of the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% in a real-life setting. METHODS: Intraocular pressure (IOP) was recorded for each eye at baseline (any previous therapy or untreated) and 4-16 weeks after changing medical treatment to or initiating treatment with the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5%. Change in IOP was evaluated over the study period for all patients and for specific pretreatment subgroups. Clinical signs such as conjunctival hyperemia and lid-parallel conjunctival folds (LIPCOF) were recorded using standardized comparative photographs. Corneal staining, subjective symptoms and local comfort were measured using a four-step scale. All adverse events were recorded. RESULTS: Among 1,157 patients enrolled, 1,075 patients were treated with the preservative-free fixed combination as the only medication at the final visit. Medical treatment was initiated in 741 patients because of an insufficient IOP-lowering effect of the prior medication. In 343 patients, medication was changed because of tolerability issues. The preservative-free fixed combination lowered IOP significantly in the subgroup of naïve patients, all subgroups with prior monotherapy and patients with prior fixed combinations: naïve patients: -8.9 mmHg, alpha- 2-agonists: -6.4 mmHg, beta-blockers: -5.7 mmHg, carbonic anhydrase inhibitors: -5.2 mmHg, prostaglandins: -4.7 mmHg, fixed-combination prostaglandins/timolol: -2.4 mmHg. At the final visit, clinical signs and subjective symptoms were improved in patients with prior medical therapy. Local comfort was rated as "very good" or "good" by 89.1% of patients at the final visit. Only few adverse events occurred during the treatment period. CONCLUSION: The preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% was effective, well tolerated and showed a good safety profile.

Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials.

INTRODUCTION: Glaucoma patients frequently exhibit ocular surface side effects during treatment with prostaglandin eye drops. The present work investigated whether glaucoma patients suffering from signs and symptoms of ocular surface disease while using preserved latanoprost eye drops benefited from switching to preservative-free tafluprost eye drops. PATIENTS AND METHODS: The analysis was based on 339 glaucoma patients enrolled in two Phase IIIb trials. The patients were required to have two symptoms, or one sign and one symptom of ocular surface disease at baseline, and at least 6 months preceding treatment with latanoprost eye drops preserved with benzalkonium chloride. All eligible patients were switched from latanoprost to preservative-free tafluprost for a total of 12 weeks. Ocular symptoms and ocular signs were evaluated at baseline and at 2 weeks, 6 weeks, and 12 weeks after commencing treatment with tafluprost. Intraocular pressure (IOP), drop discomfort, and treatment preference were evaluated to investigate the clinical efficacy and patient-related outcomes. RESULTS: After 12 weeks of treatment with preservative-free tafluprost, the incidences of irritation/burning/stinging, foreign body sensation, tearing, itching, and dry eye sensation had diminished to one-third of those reported for preserved latanoprost at baseline. The incidences of blepharitis and corneal/conjunctival fluorescein staining had in turn decreased to one-half of those reported for preserved latanoprost. Severity of conjunctival hyperemia was halved during treatment with preservative-free tafluprost, and there was significant improvement in tear break-up time and tear production. A further reduction in IOP (~1 mmHg) was seen with preservative-free tafluprost compared with preserved latanoprost. Drop discomfort was alleviated during preservative-free tafluprost treatment, and an outstanding majority of patients (72%) preferred preservative-free tafluprost over preserved latanoprost. CONCLUSION: This meta-analysis confirmed that IOP remained at the same level after replacing benzalkonium chloride-preserved latanoprost eye drops with preservative-free tafluprost eye drops. Preservative-free tafluprost significantly decreased the symptoms and signs of ocular surface disease and outrated latanoprost in drop comfort and treatment preference.

Pharmacokinetics, Efficacy, and Safety of the Preservative-free Fixed Combination of Tafluprost 0.0015% and Timolol 0.5% in Healthy Volunteers: A Phase I Comparison vs. the Corresponding Preservative-free Monotherapies.

PURPOSE: Plasma concentrations of tafluprost acid and timolol were compared after single (Day 1) and repeated (Day 8) instillations of once-daily tafluprost 0.0015%-timolol 0.5% preservative-free (PF) fixed-dose combination (FDC), once-daily PF tafluprost 0.0015%, and twice-daily PF timolol 0.5%. PATIENTS AND METHODS: Fifteen healthy volunteers were randomized to this double-masked, single-center, three-period cross-over study. A wash-out interval of at least 4 weeks separated each three 8-day dosing period. Blood samples were drawn on the first and last day of each dosing period, prior to the morning dose, as well as 5, 10, 15, 30, and 45 min, and 1, 1.5, 2, 4, 8, and 12 h post-dosing. Sample plasma concentrations of tafluprost acid and/or timolol were determined and maximum concentration (C max), area under the concentration-over-time curve from time zero to the last time point with a quantifiable measurement (AUC0-last), and time to maximum concentration were calculated. Intraocular pressure (IOP), adverse events, and ocular/systemic safety variables were also evaluated. RESULTS: Plasma concentrations of tafluprost acid were low, with similar levels measured subsequent to either single or repeated dosing of PF FDC and PF tafluprost. On both sampling days, concentrations peaked at 10 min after the dose, and were cleared from the blood circulation by 30 min; average C max ranged from 17 to 24 pg/mL, and AUC0-last from 3 to 5 pg*h/mL. Plasma concentrations of timolol were comparable after the first dose of PF FDC or PF timolol. Concentrations peaked at 15 min post-dose and diminished in a similar manner after 2 h; average C max was 800 pg/mL and AUC0-last 3900 pg*h/mL. As expected, PF timolol produced a higher Day 8 pre-dose timolol concentration than PF FDC (235 vs. 37 pg/mL; p < 0.001, respectively). The Day 8 post-dose changes in timolol concentrations were relative to this pre-dose difference. All study treatments were well tolerated and safe. PF FDC seemed to provide the best IOP reduction. CONCLUSIONS: PF FDC demonstrated good IOP-lowering efficacy and displayed similar pharmacokinetic characteristics to the monotherapy agents. Exposure to timolol was reduced via the halved dosing.

Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma.

We investigated the intraocular pressure (IOP) lowering efficacy of preservative-free fixed and non-fixed combination of tafluprost 0.0015% and timolol 0.5% in pseudoexfoliative glaucoma (XFG). A per protocol worse eye analysis was made on all XFG patients who participated in a recent 6 month, prospective, randomized, double-masked, parallel group, multicenter phase III study. The mean time-wise IOP decreased by 8.62 to 10.25 mmHg (31.8 to 36.7%) in the fixed dose combination arm (15 patients) and by 5.38 to 11.35 mmHg (21.3 to 41.2%) in the non-fixed combination arm (13 patients), respectively (p < 0.001 for all comparisons). The results show that a preservative-free fixed dose combination of tafluprost and timolol provides a clinically significant IOP reduction in XFG, and may offer an advantage for the XFG patients with dry eye, due to its preservative-free nature.

A 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components.

INTRODUCTION: The efficacy, safety and tolerability of the preservative-free (PF) fixed combination (FC) of tafluprost 0.0015% and timolol 0.5% (once daily) were compared to those of the individual components (PF tafluprost 0.0015% once daily and PF timolol 0.5% twice daily) in patients with open-angle glaucoma or ocular hypertension inadequately controlled on prior timolol or prostaglandin monotherapy for 6 months. METHODS: A stratified, double-masked, randomized, multicenter phase III study was conducted. A total of 189 prior timolol users were randomized within the timolol stratum (TS) to receive either FC (n = 95) or timolol 0.5% (TIM; n = 94). Furthermore, a total of 375 prior prostaglandin analog (PGA) users were randomized within the prostaglandin stratum (PS) to receive either FC (n = 188) or tafluprost 0.0015% (TAF; n = 187). To be eligible for participation in the study, the patients were required to have an intraocular pressure (IOP) of ≥22 mmHg when on timolol (TIM) or of ≥20 mmHg when on PGA in either treated eye at the screening and end-of-run-in visits. In addition to these, the study included visits at baseline, 2 and 6 weeks, 3 and 6 months and at a post-study visit. IOP was measured at 8 a.m., 10 a.m., 4 p.m., and 8 p.m. RESULTS: In the TS, a significant reduction from baseline IOP was seen with FC and TIM throughout the study. Average diurnal IOP change from baseline at month 3 was -8.55 mmHg (32%) for FC and -7.35 mmHg (28%) for TIM. The model-based treatment difference (FC-TIM) was -0.885 mmHg [95% confidence interval (CI) -1.745 to -0.024; p = 0.044] demonstrating the superiority of FC over TIM. In the PS, a significant reduction in IOP was seen with both FC and TAF throughout the study. The average diurnal IOP change from baseline at month 3 was -8.61 mmHg (33%) for FC and -7.23 mmHg (28%) for TAF. The model-based treatment difference (FC-TAF) was -1.516 mmHg (95% CI -2.044 to -0.988; p < 0.001) demonstrating the superiority of FC over TAF. In the TS, related ocular adverse events (AEs) were more frequent for patients treated with FC compared to TIM (16.8% versus 6.4%), whereas related non-ocular AEs were more frequent with TIM compared to FC (2.1% versus 0.0%). In the PS, AEs were similarly distributed between FC and TAF. The frequency of conjunctival hyperemia of FC was low (6.4%). CONCLUSION: The preservative-free fixed combination of tafluprost and timolol provided a substantial and significant IOP reduction in both strata. The IOP reduction was superior to both tafluprost 0.0015% and timolol 0.5% when given as monotherapies. Overall, the study treatments were safe and well tolerated. FUNDING: Santen Oy, Tampere, Finland.

Fixed-dose combination of tafluprost and timolol in the treatment of open-angle glaucoma and ocular hypertension: comparison with other fixed-combination products.

A new preservative-free fixed-dose combination of 0.0015% tafluprost, a prostaglandin F2α analog, and 0.5% timolol (TAF/TIM; Santen Oy, Tampere, Finland), a beta-adrenergic antagonist has recently been developed. The intraocular pressure (IOP) reduction with TAF/TIM in open-angle glaucoma and ocular hypertension is similar to that of other prostaglandin-timolol fixed-combination products. Patients with high IOP responded well to TAF/TIM with reductions of up to 40% (>13 mmHg) and beyond. Compared to previous controlled and double-masked clinical trials with DuoTrav(®) (Alcon, Fort Worth, USA) and Ganfort(®) (Allergan, Irvine, USA), TAF/TIM caused less superficial ocular side effects and less conjunctival hyperemia. Plausible explanations for the differences in side effects between the fixed-combination products are discussed.

Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% versus concomitant use of the ingredients.

PURPOSE: To compare efficacy, safety, and tolerability of the preservative-free fixed combination (FC) and non-fixed combination (NFC) of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. METHODS: This 6-month, prospective, randomized, double-masked, active-controlled, parallel group, multicenter phase III study was performed in patients with ocular hypertension and open-angle glaucoma with untreated intraocular pressure (IOP) ≥23 and ≤36 mmHg at baseline. RESULTS: Four hundred patients washed out from IOP-lowering medication were randomized, 201 received the FC, and 199 received the NFC. Mean time-wise IOP decreases from baseline ranged from -7.3 to -9.1 mmHg (29.6%-34.6%) in the FC and from -7.5 to -9.4 mmHg (30.7%-36.0%) in the NFC arm [per-protocol (PP) dataset, P<0.0001 compared with baseline for both groups]. At month 6, the estimated overall treatment difference (FC-NFC) was 0.308 mmHg (PP dataset, 95% confidence interval from -0.194 to 0.810 mmHg). An IOP decrease ≥30% was achieved in 58.3% and 66.9% of the patients in the FC and NFC groups, respectively (PP dataset; P=0.105); an IOP decrease ≥35% was achieved in 36.6% and 43.1% of patients in the FC and NFC groups, respectively (PP dataset; P=0.297). Patients with ocular adverse events were evenly distributed in both groups. The most common side effect, conjunctival/ocular hyperemia was found in 8% and 5% of patients in the FC and NFC arms, respectively. CONCLUSIONS: All measures of IOP reduction for FC of preservative-free tafluprost/timolol were statistically and clinically significant and non-inferior to those of the NFC, throughout the 6-month study period.

Handling test of eye drop dispenser--comparison of unit-dose pipettes with conventional eye drop bottles.

PURPOSE: The aims of this study were to investigate how elderly people handle single-use eye drop dispensers (unit-dose pipettes) and to compare the performance with conventional eye drop bottles. METHODS: In this open-label study, the handling of unit-dose pipettes and conventional eye drop bottles was compared in 41 elderly people who had little or no prior regular use of eye drop dispensers. The participants tested both types of dispenser once, and the following 7 variables were studied: ease/difficulty of opening the dispenser; influence of the size for handling of the dispenser; influence of the shape for handling of the dispenser; observation of the contents in the dispenser; the feeling of the dispenser in the hand; ease/difficulty of drop instillation on the eye from the dispenser; and overall performance of the eye drop dispenser. The dispensers contained isotonic saline, and a visual analog scale was used for assessment of each of the above variables. RESULTS: The mean age of the participants was 73 years. A statistically significant difference in favor of the unit-dose pipettes was found with respect to observation of the contents in the dispenser, ease of administration, and the overall performance. Women regarded the unit-dose pipettes generally better than the bottles, but such a difference was not seen in men. CONCLUSIONS: The study participants managed the unit-dose pipettes at least as well as the conventional eye drop bottles. If anything, the unit-dose pipettes appeared to be easier to use.

Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication.

PURPOSE: The purpose of this study was to investigate the tolerability and intraocular pressure (IOP) reducing effect of the first preservative-free prostaglandin tafluprost (Taflotan) in patients exhibiting ocular surface side-effects during latanoprost (Xalatan) treatment. METHODS: A total of 158 patients were enrolled in this open-label multicentre study. Eligible patients had to have at least two ocular symptoms, or one sign and one symptom, during treatment with latanoprost. At baseline, the patients were directly switched from latanoprost to preservative-free tafluprost for 12 weeks. The patients were queried for ocular symptoms, and ocular signs were assessed by using tear break-up time, Schirmer's test, fluorescein staining and evaluation of conjunctival hyperaemia and blepharitis. In addition, HLA-DR and MUC5AC in conjunctival impression cytology specimens were analyzed, and a drop discomfort/quality of life (QoL) questionnaire was employed. IOP was measured at all visits. RESULTS: Preservative-free tafluprost maintained IOP at the same level after 12- weeks treatment (16.4 +/- 2.7 mmHg) as latanoprost at baseline (16.8 +/- 2.5 mmHg). During treatment with preservative-free tafluprost, the number of patients having irritation/burning/stinging (56.3%), itching (46.8%), foreign body sensation (49.4%), tearing (55.1%) and dry eye sensation (64.6%) decreased to 28.4%, 26.5%, 27.1%, 27.1% and 39.4% correspondingly. The number of the patients with abnormal fluorescein staining of cornea (81.6%) and conjunctiva (84.2%), blepharitis (60.1%), conjunctival hyperaemia (84.2%) and abnormal Schirmer's test (71.5%) was also reduced significantly to 40.6%, 43.2%, 40.6%, 60.0% and 59.4% correspondingly. The tear break-up time improved significantly from 4.5 +/- 2.5 seconds to 7.8 +/- 4.9 seconds. A reduction in the number of patients with abnormal conjunctival cells based on HLA-DR and MUC5AC was also detected. CONCLUSIONS: Preservative-free tafluprost maintained IOP at the same level as latanoprost, but was better tolerated in patients having signs or symptoms while on preserved latanoprost. Preservative-free tafluprost treatment resulted in improved QoL, increased patient satisfaction and drop comfort.

Efficacy and safety of tafluprost 0.0015% versus latanoprost 0.005% eye drops in open-angle glaucoma and ocular hypertension: 24-month results of a randomized, double-masked phase III study.

PURPOSE: The objective of the study was to compare the long-term efficacy and safety of tafluprost 0.0015% with latanoprost 0.005% eye drops in patients with open-angle glaucoma or ocular hypertension. METHODS: This double-masked, active-controlled, parallel-group, multinational, multicentre, phase III study was conducted at 49 centres in 8 countries. Eligible patients were assigned to treatment administered once daily at 20:00 hrs for up to 24 months. Change from baseline intraocular pressure (IOP) was the primary efficacy variable. Adverse events were recorded and ocular safety was evaluated. Both tafluprost and latanoprost were preserved with benzalkonium chloride. RESULTS: From 533 patients randomized, 402 patients completed 24 months of therapy. Both treatments had a substantial IOP-lowering effect which persisted throughout the study (-7.1 mmHg for tafluprost and -7.7 mmHg for latanoprost at 24 months). Although the IOP-lowering effect during the study was slightly larger with latanoprost, this difference was clinically small and the noninferiority of tafluprost to latanoprost over all diurnal IOP measurements was shown with anova and almost reached with ancova (upper limits of the 95% confidence intervals 1.38 and 1.52 for the overall period, respectively). The noninferiority limit was 1.5 mmHg. CONCLUSIONS: Tafluprost is a new effective and well-tolerated treatment for glaucoma and ocular hypertension.

A phase II study on the duration and stability of the intraocular pressure-lowering effect and tolerability of Tafluprost compared with latanoprost.

PURPOSE: Tafluprost is a novel prostaglandin F(2alpha)-receptor agonist shown to lower intraocular pressure (IOP) in healthy humans and patients with elevated IOP. We investigated the efficacy, safety, and tolerability of tafluprost 0.0015% compared with latanoprost 0.005% in patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension. METHODS: This was a randomized, double-masked, active-controlled, parallel-group, multinational, and multicenter phase II study. Patients received either tafluprost 0.0015% (n = 19) or latanoprost 0.005% (n = 19), both once daily. The extent and duration of action of the IOP-lowering effects at Day 42 and Day 43 were the primary efficacy endpoints. Efficacy and safety parameters were analyzed throughout. RESULTS: Maximum IOP reduction was achieved by Day 7 and was sustained until Day 42 in both groups (mean [standard deviation] change from baseline -9.7 [3.3] mm Hg for tafluprost and -8.8 [4.3] mm Hg for latanoprost). The overall treatment group difference was 0.17 mm Hg (95% confidence interval -1.27 to 1.61; P = 0.811). The IOP-lowering effect was maintained for >or=24 h after the last dose in both groups. Most adverse events were ocular and were similar in frequency and severity between groups. There were 3 severe adverse events, all ocular, and all in the tafluprost group (3/19 = 16%). CONCLUSIONS: Tafluprost and latanoprost have comparable effects on the extent, duration, and stability of IOP reduction, and are well tolerated in patients.

Adjunctive use of tafluprost with timolol provides additive effects for reduction of intraocular pressure in patients with glaucoma.

PURPOSE: This study investigated the efficacy and safety of tafluprost as an adjunctive therapy to timolol in patients with open-angle glaucoma or ocular hypertension, uncontrolled by timolol monotherapy. METHODS: This was a randomized, double-masked, parallel-group, multinational and multicenter 12-week phase III study. Tafluprost 0.0015% (once daily: 20:10) or vehicle were administered as adjunctive therapy to timolol 0.5% (twice daily: 08:00 and 20:00) for 6 weeks, after which all patients received tafluprost for 6 weeks. Intraocular pressure (IOP) measurements were conducted at 08:00, 10:00, and 16:00 at baseline, and weeks 2, 4, 6, and 12. RESULTS: A total of 185 patients were randomized to tafluprost (n = 96) or vehicle (n = 89). Reductions in IOP were seen in both groups, which were consistently more pronounced with tafluprost. At week 6, the change from baseline in diurnal IOP ranged from -5.49 to -5.82 mmHg, and the overall treatment difference (tafluprost vehicle) was -1.49 mmHg (upper 95% confidence interval, -0.66; p<0.001, intention-to-treat population, repeated measurements of the analysis of covariance model). At week 12, the change from baseline ranged from -6.22 to -6.79 mmHg in the tafluprost group. Patients switched from vehicle to tafluprost achieved a similar decrease in IOP to those who received tafluprost throughout the study (group difference at 12 weeks, -0.09 mmHg, p=0.812). There were more ocular adverse events with tafluprost compared with vehicle (42% vs. 29%, respectively), but most were mild in severity. CONCLUSIONS: As adjunctive therapy to timolol, tafluprost achieved a consistently greater reduction in IOP compared with vehicle, and was well tolerated.

Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor.

Ophthalmic timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% timolol in patients scheduled for a cataract operation. The concentration in the aqueous humor was 210+/-175 ng/ml (mean+/-S.D.) 2h after administration of timolol 0.1% hydrogel and 538+/-304 ng/ml after aqueous 0.5% timolol. In the aqueous 0.5% timolol group more patients had unnecessarily high concentrations of timolol in the aqueous humor. beta(1)-receptors and beta(2)-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of timolol in the aqeuous 0.5% timolol group. In conclusion, in contrast to the conventional aqueous 0.5% timolol, 0.1% timolol hydrogel caused only slight inter-individual variation in timolol concentration in the aqueous humor.

Increased anterior chamber penetration of topical levofloxacin 0.5% after pulsed dosing in cataract patients.

PURPOSE: This study aimed to investigate the rise in aqueous humour (AH) levels of levofloxacin after a specific perioperative pulsed topical drop regimen. METHODS: Thirty patients undergoing phacoemulsification surgery were administered two preoperative drops of levofloxacin 0.5%, 30 mins apart, and three pulsed drops postoperatively, 5 mins apart. Aqueous humour levels of levofloxacin were measured at the start of surgery and from 5 mins to 90 mins after the last postoperative drop. Samples from individual patients were collected at the time of surgery and at one additional sampling interval by aqueous tap, and analysed using a high-performance liquid chromatography assay. RESULTS: Aqueous humour levels of levofloxacin continued to rise gradually, reaching a mean peak level (C(max)) of 4.4 microg/ml (+/- 2.5) at 60 mins after the last postoperative drop was administered. This level exceeded the minimum inhibitory concentration of common ocular pathogens at least fourfold. At 90 mins after the last drop, mean AH levels remained > 3 microg/ml. CONCLUSIONS: This is the first study to measure AH levels of levofloxacin after postoperative pulsed dosing in humans. Higher AH levels were found than in previously reported studies in which only preoperative drops were given and levels were measured at the time of surgery. Levels of levofloxacin continued to rise for 60 mins after administration of the last postoperative drop, demonstrating that delivery and maintenance of effective antibiotic levels may be achievable with alternative dosing schedules.

Pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost in healthy volunteers.

PURPOSE: Prostanoid F(2alpha) (PF(2alpha)) analogues are commonly used as first-line treatment of glaucoma. Tafluprost is a newly synthesized PF(2alpha) derivative and represents the first PF(2alpha) analogue with a fully preservative-free formulation. METHODS: A randomized, investigator-masked, single-centre, crossover phase I study evaluated the pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost 0.0015% eyedrops in healthy volunteers. Both formulations were administered once/day for 8 days each. Plasma concentrations and, consequently, area under the curve (AUC(0-last)), maximum concentration (C(max)) and time to maximum concentration (t(max)) were determined for tafluprost acid, the biologically active metabolite. Intraocular pressure, adverse events, and ocular and systemic safety parameters were analysed. RESULTS: There were no statistically significant differences in pharmacokinetic parameters between preserved and preservative-free formulations after either single (day 1) or repeated (day 8) dosing. The mean (+/- standard deviation) results for preserved and preservative-free formulations on day 8 were, respectively: AUC(0-last) 581.1 +/- 529.9 pg/min/ml versus 431.9 +/- 457.8 pg/min/ml (p = 0.462); C(max) 31.4 +/- 19.5 pg/ml versus 26.6 +/- 18.0 pg/ml (p = 0.294), and median (range) t(max) 10 (5-15) for both. Generally, plasma concentrations of tafluprost acid were low at all time-points and were cleared rapidly from the circulatory system. There were no unexpected safety findings. The incidence of ocular hyperaemia was similar in both formulations and was of predominantly moderate severity with preserved tafluprost and mild severity with preservative-free tafluprost. CONCLUSIONS: Preservative-free tafluprost appeared to have similar pharmacokinetic properties to the preserved formulation and was generally well tolerated.

Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypertension: results from a pharmacodynamics analysis.

PURPOSE: Tafluprost is a new prostaglandin F(2alpha) (PGF(2alpha)) derivative in development for the treatment of glaucoma. Tafluprost is the first PGF(2alpha) analogue with a preservative-free formulation. METHODS: This randomized, investigator-masked, multicentre, crossover phase III study evaluated the pharmacodynamics and safety of preserved and preservative-free tafluprost 0.0015% eyedrops administered for 4 weeks in 43 patients with open-angle glaucoma or ocular hypertension. The primary variable was change from baseline in overall diurnal intraocular pressure (IOP) at 4 weeks. Adverse events and other safety parameters were also analysed. RESULTS: Decreased IOP was clearly observed with both formulations at week 1 and was sustained until week 4. The overall treatment difference (preservative-free versus preserved formulations) at week 4 was 0.01 mmHg (95% confidence interval - 0.46 to 0.49; p = 0.96). There were no unexpected safety-related findings. Both formulations were well tolerated and most adverse events were ocular and mild in severity. CONCLUSIONS: THE reduction in IOP achieved by preservative-free tafluprost is equivalent to that obtained with the preserved formulation. The preservative-free formulation was generally well tolerated.

A comparative, placebo-controlled study of prostanoid fluoroprostaglandin-receptor agonists tafluprost and latanoprost in healthy males.

OBJECTIVE: The aim of this study was to determine the safety, tolerability, and pharmaco-dynamics of a novel prostanoid fluoroprostaglandin (FP)-receptor agonist, tafluprost (AFP-168), in healthy males. METHODS: This was a phase I study in healthy males 18-45 years of age (N = 49). Participants were randomized to receive 1 of 4 eye drops: tafluprost 0.0025% or 0.005%, latanoprost 0.005%, or a placebo, administered once-daily for 7 days, with 1 drop per eye. Safety and tolerability assessments and intraocular pressure (IOP) measurements were performed at defined intervals. RESULTS: Tafluprost was generally well tolerated. No serious adverse events were reported and no participants withdrew owing to an adverse event. IOP decreased over time, compared with baseline, in all 4 treatment groups. Treatment with tafluprost 0.005% resulted in a significantly greater reduction in IOP, compared with either latanoprost 0.005% or a placebo, at various time points during treatment. Ocular hyperemia and photophobia were more common with tafluprost 0.0025% or 0.005%, compared with latanoprost 0.005%. CONCLUSIONS: Tafluprost eye drops 0.0025% and 0.005% were generally well tolerated and safe. Tafluprost 0.005% reduced IOP more than placebo or latanoprost 0.005%. Therefore, tafluprost looks promising for further investigation.